{"title":"Unlocking the power of non-coding RNAs: toward real-time cancer monitoring in precision oncology.","authors":"Manon Chang,Thomas Papazyan,Elvire Pons-Tostivint,Delphine Fradin","doi":"10.1186/s12943-025-02536-y","DOIUrl":"https://doi.org/10.1186/s12943-025-02536-y","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"19 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1186/s12943-025-02492-7
Ran Zhou, Yuejun Li, Guanghui Li, Yan Li, Lie Luo, Bin Wang, Liping Wang
Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC present significant challenges to global public health. As the primary metabolic organ in the human body, the liver undergoes substantial metabolic reprogramming during carcinogenesis, affecting various metabolic pathways including those involved in carbohydrates, lipids, and amino acids. Notably, disruptions in amino acid metabolism play a critical role in the initiation and progression of HCC, helping to sustain its malignant characteristics. This review aims to provide an in-depth analysis of the alterations observed in aromatic amino acids metabolism, branched chain amino acids (BCAAs) metabolism, glutamine metabolism, and other amino acid metabolism processes, including serine, arginine, and methionine, along with the expression patterns of associated metabolic enzymes. Furthermore, it discusses potential therapeutic approaches and their clinical relevance, offering insights and strategies for improving HCC diagnosis and treatment in the future.
{"title":"Metabolic characteristics in hepatocellular carcinoma: amino acid metabolic reprogramming.","authors":"Ran Zhou, Yuejun Li, Guanghui Li, Yan Li, Lie Luo, Bin Wang, Liping Wang","doi":"10.1186/s12943-025-02492-7","DOIUrl":"10.1186/s12943-025-02492-7","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is a common type of primary liver cancer and is considered the third leading cause of cancer-related deaths worldwide. The high aggressiveness and resistance to therapies exhibited by HCC present significant challenges to global public health. As the primary metabolic organ in the human body, the liver undergoes substantial metabolic reprogramming during carcinogenesis, affecting various metabolic pathways including those involved in carbohydrates, lipids, and amino acids. Notably, disruptions in amino acid metabolism play a critical role in the initiation and progression of HCC, helping to sustain its malignant characteristics. This review aims to provide an in-depth analysis of the alterations observed in aromatic amino acids metabolism, branched chain amino acids (BCAAs) metabolism, glutamine metabolism, and other amino acid metabolism processes, including serine, arginine, and methionine, along with the expression patterns of associated metabolic enzymes. Furthermore, it discusses potential therapeutic approaches and their clinical relevance, offering insights and strategies for improving HCC diagnosis and treatment in the future.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":" ","pages":"25"},"PeriodicalIF":33.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12882192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-07DOI: 10.1186/s12943-025-02510-8
Haran Sivakumaran, Sneha Nair, Mainá Bitar, Xue Lu, Lu Wang, Ji Liu, Deshapriya S Karunarathne, P Prakrithi, Sebastien Jacquelin, Isela Sarahi Rivera, Kristine M Hillman, Susanne Kaufmann, Rebekah Ziegman, Wei Shi, Sarah Alexandrou, C Elizabeth Caldon, Rakesh N Veedu, Quan H Nguyen, Jonathan Beesley, Michelle N Wykes, Juliet D French, Stacey L Edwards
Background: Interferons (IFNs) are key cytokines that drive immune responses against infections and cancer, yet few therapies have successfully leveraged IFN signaling for cancer treatment. Long noncoding RNAs (lncRNAs) are emerging as promising therapeutic candidates, but their roles in immune modulation remain largely unexplored. Here, we functionally characterize a breast cancer-associated lncRNA, BRRIAR, which primes the IFN signaling pathway in specific cancer contexts and represents a potential therapeutic strategy for estrogen receptor-positive (ER+) breast cancer.
Methods: BRRIAR expression and subcellular localization were examined using qPCR, in situ hybridization, single-cell RNA sequencing and spatial transcriptomics. BRRIAR target genes were identified through CRISPR interference, chromatin interaction assays and ChIP sequencing. Mechanistic studies in ER + breast cancer cells included CRISPR-Cas9 genome-wide screens, RNA sequencing, RNA pull-down followed by mass spectrometry, proliferation assays and Western blotting. The therapeutic potential of BRRIAR was evaluated via intratumoral delivery of lipid nanoparticle-encapsulated BRRIAR in ER + breast cancer xenograft models. Immune activation was assessed using flow cytometry and cytokine profiling of human peripheral blood mononuclear cells (PBMCs).
Results: We demonstrate that BRRIAR is a key target gene at the 3p26 breast cancer risk region. Primarily expressed in ER + breast tumors, BRRIAR acts both in cis and in trans. Nuclear BRRIAR regulates BHLHE40 expression in cis through chromatin interactions, while cytoplasmic BRRIAR binds in trans to the pattern recognition receptor RIG-I, priming IFN signaling. Overexpression of BRRIAR RNA triggers RIG-I signaling, inducing IFN responses, drives rapid, dose-dependent apoptosis of ER + breast cancer cells in vitro and in vivo, and promotes immune activation in human PBMCs.
Conclusions: These findings establish lncRNAs as key regulators of tumor immunity and uncover a critical link between genetic risk, lncRNAs, cancer immunosurveillance and breast cancer development, positioning BRRIAR as a promising lncRNA-based RIG-I activator for ER + breast cancer therapy.
{"title":"BRRIAR lncRNA alters breast cancer risk by modulating interferon signaling in cis and in trans.","authors":"Haran Sivakumaran, Sneha Nair, Mainá Bitar, Xue Lu, Lu Wang, Ji Liu, Deshapriya S Karunarathne, P Prakrithi, Sebastien Jacquelin, Isela Sarahi Rivera, Kristine M Hillman, Susanne Kaufmann, Rebekah Ziegman, Wei Shi, Sarah Alexandrou, C Elizabeth Caldon, Rakesh N Veedu, Quan H Nguyen, Jonathan Beesley, Michelle N Wykes, Juliet D French, Stacey L Edwards","doi":"10.1186/s12943-025-02510-8","DOIUrl":"10.1186/s12943-025-02510-8","url":null,"abstract":"<p><strong>Background: </strong>Interferons (IFNs) are key cytokines that drive immune responses against infections and cancer, yet few therapies have successfully leveraged IFN signaling for cancer treatment. Long noncoding RNAs (lncRNAs) are emerging as promising therapeutic candidates, but their roles in immune modulation remain largely unexplored. Here, we functionally characterize a breast cancer-associated lncRNA, BRRIAR, which primes the IFN signaling pathway in specific cancer contexts and represents a potential therapeutic strategy for estrogen receptor-positive (ER+) breast cancer.</p><p><strong>Methods: </strong>BRRIAR expression and subcellular localization were examined using qPCR, in situ hybridization, single-cell RNA sequencing and spatial transcriptomics. BRRIAR target genes were identified through CRISPR interference, chromatin interaction assays and ChIP sequencing. Mechanistic studies in ER + breast cancer cells included CRISPR-Cas9 genome-wide screens, RNA sequencing, RNA pull-down followed by mass spectrometry, proliferation assays and Western blotting. The therapeutic potential of BRRIAR was evaluated via intratumoral delivery of lipid nanoparticle-encapsulated BRRIAR in ER + breast cancer xenograft models. Immune activation was assessed using flow cytometry and cytokine profiling of human peripheral blood mononuclear cells (PBMCs).</p><p><strong>Results: </strong>We demonstrate that BRRIAR is a key target gene at the 3p26 breast cancer risk region. Primarily expressed in ER + breast tumors, BRRIAR acts both in cis and in trans. Nuclear BRRIAR regulates BHLHE40 expression in cis through chromatin interactions, while cytoplasmic BRRIAR binds in trans to the pattern recognition receptor RIG-I, priming IFN signaling. Overexpression of BRRIAR RNA triggers RIG-I signaling, inducing IFN responses, drives rapid, dose-dependent apoptosis of ER + breast cancer cells in vitro and in vivo, and promotes immune activation in human PBMCs.</p><p><strong>Conclusions: </strong>These findings establish lncRNAs as key regulators of tumor immunity and uncover a critical link between genetic risk, lncRNAs, cancer immunosurveillance and breast cancer development, positioning BRRIAR as a promising lncRNA-based RIG-I activator for ER + breast cancer therapy.</p>","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":"5"},"PeriodicalIF":33.9,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12777463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-06DOI: 10.1186/s12943-025-02550-0
Hongyu Li, Bing Su, Yan Jiang, Boyang Zhang, Rulong Du, Can Song, Bin Hou, Kun Xu, Lida Wu, Yuchun Gu
{"title":"Retraction Note: Circular RNA circDCUN1D4 suppresses hepatocellular carcinoma development via targeting the miR-590-5p/ TIMP3 axis.","authors":"Hongyu Li, Bing Su, Yan Jiang, Boyang Zhang, Rulong Du, Can Song, Bin Hou, Kun Xu, Lida Wu, Yuchun Gu","doi":"10.1186/s12943-025-02550-0","DOIUrl":"10.1186/s12943-025-02550-0","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"25 1","pages":"4"},"PeriodicalIF":33.9,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12771894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145912459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The puppet master in the breast cancer \"microecological community\": spatial and metabolic regulation of macrophage heterogeneity.","authors":"Hao Wu,Hong-Da Tian,Liuying Zhao,Dandan Liu,Baohang Lin,Xiaohong Wu","doi":"10.1186/s12943-025-02551-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02551-z","url":null,"abstract":"","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"30 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lactate, traditionally considered just a byproduct of metabolism, is now understood to be a vital regulator in energy metabolism, immune function, and epigenetic changes. Besides serving as an alternative energy source through the "lactate shuttle," it acts as a signaling molecule influencing both normal and abnormal processes in various organs. New research has emphasized its role in lactylation of histones and non-histones, a novel post-translational modification linking metabolic activity with gene expression and immune response. Lactate contributes to immunosuppression, angiogenesis, and the spread of tumors within the tumor microenvironment. Its accumulation is also linked to cardiovascular, metabolic, and neurodegenerative conditions. This shift in metabolism underscores lactate's growing importance in both health and disease, presenting novel therapeutic opportunities, especially in the treatment of cancer and metabolic disorders. This review synthesizes emerging insights into lactate's multifaceted roles and discusses promising therapeutic strategies targeting lactate metabolism, transport, and downstream signaling pathways, with an emphasis on candidates advancing toward clinical translation.
{"title":"Lactate: elucidating its indispensable role in human health.","authors":"Shengxin Zhang,Jie Wang,Ziyu Xu,Ziyang Cheng,Bin Shao,Jiayun Yu","doi":"10.1186/s12943-025-02519-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02519-z","url":null,"abstract":"Lactate, traditionally considered just a byproduct of metabolism, is now understood to be a vital regulator in energy metabolism, immune function, and epigenetic changes. Besides serving as an alternative energy source through the \"lactate shuttle,\" it acts as a signaling molecule influencing both normal and abnormal processes in various organs. New research has emphasized its role in lactylation of histones and non-histones, a novel post-translational modification linking metabolic activity with gene expression and immune response. Lactate contributes to immunosuppression, angiogenesis, and the spread of tumors within the tumor microenvironment. Its accumulation is also linked to cardiovascular, metabolic, and neurodegenerative conditions. This shift in metabolism underscores lactate's growing importance in both health and disease, presenting novel therapeutic opportunities, especially in the treatment of cancer and metabolic disorders. This review synthesizes emerging insights into lactate's multifaceted roles and discusses promising therapeutic strategies targeting lactate metabolism, transport, and downstream signaling pathways, with an emphasis on candidates advancing toward clinical translation.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"22 1","pages":"2"},"PeriodicalIF":37.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDHepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown.METHODSWe compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes.RESULTSC. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1+ macrophages, exhausted CD8+ T cells and COL1A1+ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2+ liver vascular endothelial cells, respectively.CONCLUSIONThese findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.
{"title":"Integrating single cell- and spatial- resolved transcriptomics unravels the inter-tumor heterogeneity and immunosuppressive landscape in HBV- and Clonorchis sinensis-associated hepatocellular carcinoma.","authors":"Jiayun Chen,Wenmin Lu,Yanni Lou,Jing Liu,Xiwen Liao,Yunmeng Bai,Guangqing Cheng,Guangzhi Zhu,Ji Feng,Junqi Liu,Zhaoji Liu,Liqun Jia,Jing Zhou,Tao Peng,Guo-Dong Lu,Jigang Wang","doi":"10.1186/s12943-025-02381-z","DOIUrl":"https://doi.org/10.1186/s12943-025-02381-z","url":null,"abstract":"BACKGROUNDHepatocellular carcinoma (HCC) is the most common primary liver carcinoma with high lethality. Both of hepatitis B virus (HBV) and Clonorchis sinensis (C. sinensis) are critical infectious contributors to HCC development. However, the inter-tumor heterogeneity and tumor microenvironment (TME) of HCC patients with different infectious background remain largely unknown.METHODSWe compiled a cohort of 269 primary HCC patients to assess the clinical impact of C. sinensis and HBV infections on patient prognosis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomic (ST-seq) analyses were performed on tumor and adjacent normal samples from C. sinensis-associated HCC (CP), and double-infection HCC (DP) patients. Additionally, we integrated publicly available scRNA-seq and ST-seq datasets from HBV-associated (HP) patients. Immunofluorescence, immunohistochemistry and in vitro experiments were conducted to validate inter-tumor heterogeneity among the three HCC subtypes.RESULTSC. sinensis infection is significantly associated with poorer prognosis in HCC patients. Multi-omics analyses revealed distinct inter-tumor heterogeneity in epithelial, immune, and stromal compartments across different HCC subtypes. Tumor cells in the DP group exhibited more malignant marker expression, higher copy number variation scores, increased activation of p53 pathway, and worse survival outcomes. Compared with other HCC subtypes, the TME in DP samples was enriched with SPP1+ macrophages, exhausted CD8+ T cells and COL1A1+ fibroblasts. In contrast, the CP and HP groups showed higher proportions of M2-like macrophages and ENPP2+ liver vascular endothelial cells, respectively.CONCLUSIONThese findings decipher the cellular signatures and their interactions within the TME, shedding light on the inter-tumoral heterogeneity driven by different infections, and the development of targeted therapies for infectious HCC.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"30 1","pages":"3"},"PeriodicalIF":37.3,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDDouble-Negative T (DNT) cells, lacking both CD4 and CD8 expression, play critical roles in cancer immunology, and have garnered increasing attention in cancer research. However, their heterogeneity and functional diversity within the tumor microenvironment (TME) remain underexplored.METHODSIn-house and publicly available single-cell RNA sequencing (scRNA-seq) data for different cancer types were integrated after quality control and batch effect correction, followed by DNT cells separation from CD3+ T cells subtypes. Functional characteristics, intercellular communication, differentiation trajectories, regulatory networks, and clinical relevance were analyzed among different DNT subsets. Key findings were validated using multiplex immunofluorescence and spatial transcriptomics to investigate the spatial localization of DNT subsets and their interactions within the TME. Impact of γδ T cells on immunotherapy response was also assessed using MC38-based murine tumor model.RESULTSBy integrating scRNA-seq data from 2,369 samples across 23 cancer types, we established a comprehensive single-cell atlas of 157,025 high-quality DNT cells. Fourteen distinct DNT subsets (6 αβ DNT and 8 γδ T cell subsets) were identified, demonstrating tumor both type-specific and shared distribution patterns, as well as unique cell-cell interaction network within the TME. These subsets displayed specialized functional profiles, including cytotoxicity, antigen presentation, and immune modulation, indicating that the functional diversity of DNT cells is largely subset-specific rather than a manifestation of multifunctionality within a single population. We also delineated divergent trajectories for αβ DNT and γδ T cell subsets, including the functional plasticity of gut-resident γδ T cells transitioning between cytotoxic and immunosuppressive states. Notably, several DNT subsets were significantly associated with favorable clinical treatment outcomes, including improved responses to cancer immunotherapy. Consistently, depletion of γδ T cells in the murine tumor model significantly decreased the efficacy of PD-1 blockade, underscoring their critical role in therapeutic response.CONCLUSIONSOur study uncovers the previously underappreciated heterogeneity and functional diversity of DNT cells in the TME and demonstrates their profound impact on tumor progression and immunotherapy outcomes.
{"title":"A pan-cancer single cell landscape reveals heterogeneity and functional diversity of double-negative T cells.","authors":"Qing Hao,Tao Zhou,Huayun Yan,Zhixiang Ren,Wei Mao,Li-Bin Huang,Yue-Yun Chen,Yuelan Wang,Minqin Xiao,Yajiao He,Xuyang Xia,Jing Wu,Wei-Han Zhang,Hai-Ning Chen,Maoxiang Qian,Feng Zhang,Li Yang,Lunzhi Dai,Huiyuan Zhang,Canhua Huang,Yang Shu,Yu Xu,Yang Luo,Yong Peng,Heng Xu","doi":"10.1186/s12943-025-02548-8","DOIUrl":"https://doi.org/10.1186/s12943-025-02548-8","url":null,"abstract":"BACKGROUNDDouble-Negative T (DNT) cells, lacking both CD4 and CD8 expression, play critical roles in cancer immunology, and have garnered increasing attention in cancer research. However, their heterogeneity and functional diversity within the tumor microenvironment (TME) remain underexplored.METHODSIn-house and publicly available single-cell RNA sequencing (scRNA-seq) data for different cancer types were integrated after quality control and batch effect correction, followed by DNT cells separation from CD3+ T cells subtypes. Functional characteristics, intercellular communication, differentiation trajectories, regulatory networks, and clinical relevance were analyzed among different DNT subsets. Key findings were validated using multiplex immunofluorescence and spatial transcriptomics to investigate the spatial localization of DNT subsets and their interactions within the TME. Impact of γδ T cells on immunotherapy response was also assessed using MC38-based murine tumor model.RESULTSBy integrating scRNA-seq data from 2,369 samples across 23 cancer types, we established a comprehensive single-cell atlas of 157,025 high-quality DNT cells. Fourteen distinct DNT subsets (6 αβ DNT and 8 γδ T cell subsets) were identified, demonstrating tumor both type-specific and shared distribution patterns, as well as unique cell-cell interaction network within the TME. These subsets displayed specialized functional profiles, including cytotoxicity, antigen presentation, and immune modulation, indicating that the functional diversity of DNT cells is largely subset-specific rather than a manifestation of multifunctionality within a single population. We also delineated divergent trajectories for αβ DNT and γδ T cell subsets, including the functional plasticity of gut-resident γδ T cells transitioning between cytotoxic and immunosuppressive states. Notably, several DNT subsets were significantly associated with favorable clinical treatment outcomes, including improved responses to cancer immunotherapy. Consistently, depletion of γδ T cells in the murine tumor model significantly decreased the efficacy of PD-1 blockade, underscoring their critical role in therapeutic response.CONCLUSIONSOur study uncovers the previously underappreciated heterogeneity and functional diversity of DNT cells in the TME and demonstrates their profound impact on tumor progression and immunotherapy outcomes.","PeriodicalId":19000,"journal":{"name":"Molecular Cancer","volume":"34 1","pages":""},"PeriodicalIF":37.3,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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